The 95% effective dose of nalbuphine in patient-controlled intravenous analgesia for patients undergoing laparoscopic total hysterectomy compared to equivalent sufentanil: Retraction

Abstract Purpose: To evaluate the 95% effective dose of nalbuphine in patient-controlled intravenous analgesia (PCIA) by the sequential method and compare the analgesia efficacy with the equivalent dose of sufentanil on patients undergoing laparoscopic total hysterectomy. Methods: In the first part, we defined a successful analgesia as the highest VAS ≤3 in 24 hours postoperatively. On the contrary, a failed analgesia was the highest VAS>3. According to the last patient's outcome, the next patients would be given an increase or decreased dose grade. This process ended up with 9 cross-over points. In the second part, 60 patients undergoing laparoscopic total hysterectomy were selected. They were randomly divided into 2 groups (n = 30 each group): receiving sufentanil 1.78 μg/kg (group S) and nalbuphine 1.78 mg/kg (group N). PCIA pump was given at the end of the operation with 5 mL bonus loading. The total amount of PCIA was 100 mL and programmed to deliver 0.5 mL each time with a lockout interval of 15 minutes and the background infusion amount of 2 mL/h. The VAS score and Ramsay score of were collected after the operation, the number of effective pressing times of PCIA were also recorded. Adverse reactions were documented in detail. Results: The 95% effective dose of nalbuphine in PCIA on patients undergoing laparoscopic total hysterectomy was 1.78 mg/kg. There was no significant difference in VAS between the sufentanil group and the nalbuphine groups (P > .05), but the number of the use of PCIA in the group S was more than that in the group N obviously (P <.05). The group S has a lower ramsay sedation score than group N at every time point. (P <.05). The incidence of nausea and vomiting was not statistically significant differences between two groups in the first 24 hours after colonoscopy (P >  q .05). Conclusion: Nalbuphine 1.78 mg/kg in PCIA is recommended for the patients undergoing laparoscopic total hysterectomy. And nalbuphine is a reasonable alternative to sufentanil when used in PCIA.


Introduction
Severe pain after the laparoscopic gynecological surgery is experienced by up to 10% of patients. [1] This violates the principles of the Enhanced recovery after surgery (ERAS). [2] The postoperative pain can be treated with the Patient-controlled intravenous analgesia (PCIA). [3] Meanwhile, opioids help to alleviate pain after surgery. Sufentanil, an opioid, is commonly used for the PCIA and is associated with various adverse effects: respiratory depression, nausea, vomiting, pruritus, constipation and urinary retention. [4] Nalbuphine is an opioid, that blocks the m receptor, activates the k receptor, causing analgesia and sedation. [5] Use of nalbuphine carries a lower risk of the respiratory depression, nausea, vomiting, pruritus, constipation, PONV (postoperative nausea and vomiting) and urinary retention, when compared to morphine. [6] The optimal dosing of nalbuphine for the PCIA after the laparoscopic total hysterectomy, has not been determined.
We performed a nalbuphine dose finding study, for the PCIA after the laparoscopic total hysterectomy, to establish the 95% effective dose (ED95). We then compared the efficacy and safety of the newly established dosing regimen of nalbuphine, to the equivalent dosing of sufentanil, in the same patient population.

Materials and methods
This clinical study was approved by the first affiliated hospital of Zhengzhou university (2018-63) and was registered in clinical trial registration center of China (ChiCTR1800014603). The procedure followed was performed in accordance with the declaration of Helsinki. Written informed consent was obtained from all patients. The trial included patients undergoing laparoscopic total hysterectomy from July 2018 to November 2018.
The inclusion criteria were American Society of Anesthesiologist physical status I-II female patients aged 18 years to 65 years undergoing laparoscopic total hysterectomy and requiring PCIA. Exclusion criteria: (1) opioid allergy or recent use of opioids.
(3) Those who are suffering from mental illness. (4) Those who cannot understand visual analog scale (VAS). (5) Those who refuse using PCIA.
The study was divided into two parts: determination of ED95 of nalbuphine in PCIA and comparison with the equivalent of sufentanil.
2.1. ED95 of nalbuphine 2.1.1. Protocol. No patients received any drug for premedication. Anesthesia was induced with etomidate, sufentanil and cisatracurium. Following intubation and commencement of mechanical ventilation. Anesthesia was maintained with sevoflurane in oxygen as well as with a continuous infusion of refentanil. After surgery, patients were delivered to post anesthesia care unit. PCIA pump was given at the end of the surgery with 5 mL bonus loading. The PCIA pump was 100 mL composed with normal saline and nalbuphine, and programmed to deliver 0.5 mL each time with a lockout interval of 15 minutes and the background infusion amount of 2 mL/h.
After transferring back to the general ward, all patients were observed for 24 hour. Pain intensity was evaluated with a 0 to 10 VAS at rest, collected in 24 hours postoperatively by direct questioning from investigators. (VAS was scored as 0 to 10 points, where 0 points represented painless, 10 points represented most severe pain) 2.1.2. Adverse reactions. Analgesia failure was defined as the highest VAS>3 at rest in 24 hour postoperatively, and the patients would receive supplementation of pain therapy with Tramadol. If patients had nausea and vomiting, tropisetron would be given by their own request. If patients had severe adverse events, such as allergic reaction, hypotension(systolic blood pressure <90 mm Hg), respiratory depression(respiratory rate <8 per minute), hypoxemia(SpO2<90%) and unconsciousness, the use of PCIA pump would be stopped immediately.

Dixon up and down method.
The dose of nalbuphine in PCIA pump for each patient was determined by Dixon method. [7] According to the pre-test, the dose gradient was divided into 8 steps: 1.8 mg/kg, 1.6 mg/kg, 1.4 mg/kg, 1.2 mg/kg, 1.0 mg/kg, 0. 8 mg/kg, and 0.6 mg/kg. the first patient was given nalbuphine 1.8 mg/kg in PCIA. A successful analgesia was defined as the highest VAS<3 in 24 h postoperatively. In contrast, a failed analgesia was defined as the highest VAS>3. If the analgesia was successful, the next patient would be given a decreased dose grade. If the analgesia was failure, the next patient would be given an increased dose grade. The process was not stopped until there were 9 cross-over points. (a successful analgesia followed by a failed analgesia)

Comparison with sufentanil 2.2.1. Randomization and groups.
60 female patients scheduled for laparoscopic total hysterectomy and requiring PCIA were included in this prospective, randomized, double-blinded study. Following a computer generating randomization list (Excel 14.0, Microsoft), the patients were randomly divided into two groups: sufentanil group (group S, n = 30), and nalbuphine group (groupN, n = 30). The PCIA solutions were prepared by a nurse anesthetist. According to the dose of the ED95 of nalbuphine in the first part, 1.78 mg/kg nalbuphine was added into normal saline to make a total volume of 100 mL in the group N. In the group S, the equivalent dose of sufentanil (1.78ug/kg) was added into normal saline to make a total volume of 100 mL.
The anesthesia and the treatments for adverse reactions were the same as the first part.

Observation indicators.
All data were collected by 1 Anesthesitist who knew nothing about PCIA pumps. At 4, 8, 12, and 24 hour postoperatively, we used the VAS score to evaluate the pain intensity at rest by questioning directly, and extent of sedation was measured by Ramsay score. The PCIA pumps would record the effective pressing times automatically. In addition, the incidences of opioid-related side effects, such as nausea, vomiting, pruritus, and respiratory depression, were also documented in detail.
The Ramsay sedation score(RASS) was divided into six levels: restless, 1 point; patients were able to follow researchers, were calm and with directional force, 2 points; patients could respond to instructions, 3 points; patients were lethargic, but showed rapid response to stimulus of decibel sound, 4 points; patients were lethargic, and showed slow response to stimulus of decibel sound, 5 points; and patients were lethargic, and showed no response, 0 points.

SPSS
statistical software (IBM Corporation, version 22) was used for the statistical analyses. Dixon up and down method requires at least six failure-success pairs for statistical analysis. In our research, we observed 9 cross-over points. ED95 of nalbuphine was estimated by using these data to build a Probit regression model with SPSS.
The distribution of the data was checked for normality firstly. The quantitative data were summarized as the Mean ± standard deviation and compared across groups using a two independent sample t-test. Repeat measures data were analyzed by ANOVA between and within two groups. Count data are presented as proportions (%), and comparison of both groups was performed using the Chi-square test. P values <.05 were accepted as statistically significant.
The sample size of part 2 was evaluated by calculating. The main indicator was the highest VAS score in 24 hour postoperatively. The pre-experiment had 5 cases in each group. The mean ± standard deviation of Group N and Group S was 2.8 and 3.0, respectively. A sample size of 23 in each group was determined to be required for a b value of 0.10 and an a value of 0.05. Taking in to consideration the data lost and patients who could not be interviewed after surgery, we selected 30 patients in each group as the sample size to ensure that the experiment had a large enough sample size. The other 59 patients' demographic data are presented in Table 1. No statistically significant difference was noted between the 2 groups. (P > .05) The VAS score of the two groups decreased gradually in 24 hours after surgery. (Table 2) And no significant difference in the analgesic effect was found in 2 groups in each time point. (P > .05) However, the effective pressing number of group N was fewer than that of group S(P < .05). The mean (± standard deviation) administered was 12.55 ± 3.501 mg in group S, 6.47 ± 3.115 mg in group N.
The RASS of both groups decreased gradually in 24 hours after operation. (Table 2) And the group S has a lower RASS than group N at every time point. (P < .05) Adverse reactions include 20 cases of nausea and vomiting (9 cases in group N and 11cases in group N). There were no statistically significant differences between the groups (P > .05). No patient in either group had any episode of pruritus, allergic reaction, hypotension or respiratory depression in the postoperative period.

Discussion
The sequential method could evaluate the efficacy dose of drugs with few cases, but the outcome criterion must be assessed in a short time. Therefore, it is used extensively in the anesthesia study design. [8] In the first part of our study, in the patients undergoing laparoscopic gynecologic surgery, we measured the ED95 of nalbuphine in PCIA was 1.78 mg/kg by the primary outcome VAS.
Zeng [6] indicated that the analgesic intensity of nalbuphine is similar to that of morphine, and the analgesic potency ratio of sufentanil to morphine is about 1000:1. So, in the second part of our study, we compared nalbuphine 1.78 mg/kg with the equivalent dose of sufentanil 1.78ug/kg. Several studies showed nalbuphine had good analgesic effects in PCIA after surgery. [9,10] In our study, there was no difference in VAS scores between the 2 groups, but the number of the use of PCIA with sufentanil was more than that with nalbuphine. In other words, patients need less dose of nalbuphine to achieve the equal analgesic effect of sufentanil. This result may be related to the k receptor agitated by nalbuphine, which is effective in the visceral pain. [11,12] We further found the level of sedation in patients with nalbuphine was higher than that with sufentanil. Deng [13] has reported that patients receiving nalbuphine and propofol had a significantly lower propofol dose compared with patients treated with sufentanil and propofol. It may be due to the central sedation produced by nalbuphine. Notably, patients with nalbuphine was not willing to do some exercise out of bed because of the sedation. Some surgeon complaint it probably had an adverse effect on postoperative recovery. Nausea and vomiting are common complications of general anesthesia. Our findings show that the incidence of nausea and vomiting was high in all patients. But most of them responded well to antiemetics. A study has indicated that Female and abdominal surgery are risk factors for postoperative nausea and vomiting. [14] therefore, we could give these patients antiemetics preventability.
The limitations of this study are as follows. First, the sample size is relatively small, although it has been calculated from the sample size. The large clinical randomized controlled studies are needed to further confirm the result. Second, we did not measure the pain threshold in patients under normal physiological conditions or before surgery. Each person's perception of pain is different, which may influence the outcome.
In conclusion, nalbuphine 1.78 mg/kg in PCIA is recommended for the patients undergoing laparoscopic total hysterectomy. And nalbuphine is a reasonable alternative to sufentanil when used in PCIA.